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Immunology Update - Christmas 2016

Welcome to our last installment before Christmas of our regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.

New imaging technique may guide treatment of inflammatory disorders

Common variable immunodeficiency disease (CVID) is the most common severe
adult primary immunodeficiency, affecting 1 in 25,000 adults. Patients do not produce antibodies to combat infection, despite normal levels of B cells, and are at higher risk of developing inflammatory and autoimmune disorders. A subset of those diagnosed with CVID develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with poor outcome. Our understanding of GLILD pathogenesis is inadequate, and a method to monitor disease progression and guide treatment is imperative.

In a study carried out at the University Hospital of Wales, and published in Clinical  & Experimental Immunology, researchers repurposed a combined imaging technique already used for cancer imaging. The technique, called FDG PET-CT, uses the anatomical data obtained by CT scan, and overlays it with metabolic data of glucose uptake by cells in tissues. The team observed a patient with GLILD before and after combination therapy, and noticed clear improvements in both anatomical and functional activity between the metabolic images before and after treatment. The combined FDG PET-CT shows that GLILD is only the pulmonary facet of a highly metabolically active multisystem disease.

BSI member Dr Stephen Jolles, who led the study, says, “This study is the first time that the imaging technique, FDG PET-CT, has been used to assess the combined lung structure and metabolic activity in a patient with GLILD before and after treatment. The images are striking and enlightening in that they reveal the highly metabolically active multi-systemic nature of the disease. It remains to me amazing the ability of this technique to overlay structure with metabolic functional activity in this way.” It is expected that this technique will be used to inform treatment of a number of other inflammatory disorders.

Read the press release

Read the full article: Jolles et al. 2016 Clinical & Experimental Immunology doi:10.1111/cei.12856

New approach uses genetic evidence to guide drug design

Over 80 autoimmune diseases, such as type 1 diabetes, multiple sclerosis and Crohn’s disease, affect hundreds of thousands of people in the UK. There are no cures, although treatments are available to manage the symptoms. While many of these treatments suppress the immune response, they also increase the  patients’ susceptibility to opportunistic infection. A research team at the University of Oxford, which included BSI member Dr Hayley Evans, studied the genetics behind autoimmune diseases in a bid to guide drug design.

In the study, published in Science Translational Medicine, researchers conducted a meta-analysis across patients with autoimmune disorders and healthy individuals. The team identified a genetic mutation that exerts a protective effect across 10 different autoimmune diseases. A single mutation was identified in the protein non-receptor tyrosine kinase 2 (TYK2), which promotes cytokine signalling during infection. Dysregulation of cytokine signalling is understood to induce autoimmunity. To study its apparent protective effect, a mouse model of the multiple sclerosis-like disease, EAE, which was also homozygous for the TYK2 mutation, led to complete protection against the autoimmune disease. In addition, analysis of Biobank genotype resources indicated that people carrying this mutation were healthy, and no more susceptible to mycobacterial, bacterial, viral, or fungal infection. Professor Lars Fugger, who led the study, said, “We found that people carrying the protective TYK2 genetic variant were no more likely to have serious infection or to develop cancer than people without the variant.” In essence, cytokine signalling through TYK2 for those carrying genetic markers for autoimmune diseases is low enough to protect against autoimmunity, but high enough to prevent immunodeficiency.

The hope is to create a drug that mimics the effects of this mutation. Further research is needed to understand how the mutation affects TYK2 protein structure and function, and to ensure that, despite predictions, the drug does not induce unwanted side effects.

Read the press release

Read the full article: Dendrou et al. 2016 Science Translational Medicine doi: 10.1126/scitranslmed.aag1974

Weight loss condition linked to poor cancer immunotherapy outcomes

Cancer immunotherapies activate the body’s immune system to target and destroy cancer cells. While there is much potential for this method of treatment, it has only shown promise in very few patients. One possible explanation for this inconsistency has been explored by researchers at the Cancer Research UK Cambridge Institute, who have delved into the mechanism behind a weight loss condition, cachexia, which affects many cancer patients. Cancer cachexia is found in patients with advanced stages of the disease. It causes loss of appetite, weight loss, wasting, fatigue, and cannot be reversed by increasing nutritional intake.

The research, published in Cell Metabolism, identified the role of a particular protein, IL-6, released by cancer cells even before cachexia manifests. IL-6 alters the ability of the liver to respond to caloric deprivation by preventing the liver from generating available sources of energy that compensate for decreased caloric intake. This energy deficit magnifies the host stress response, releasing high levels of glucocorticoid hormone that suppresses the immune response.

Senior author, Professor Douglas Fearon, said, “The results raise the distinct possibility of future cancer therapies that are designed to target how the patient’s own body responds to cancer, with simultaneous benefit for reducing weight loss and boosting immunotherapy.”

Professor Douglas Fearon is one of the plenary speakers at the BSI/NVVI Joint Congress, taking place in Liverpool on 6 – 9 December 2016. He will give his presentation at 11:30 on Friday 9 December.

Read the press release

Read the full article: Flint et al. 2016 Cell Metabolism doi: 10.1016/j.cmet.2016.10.010

Pan-herpesvirus inhibition by small molecule inhibitor

​Herpesviruses are associated with a wide range of acute or chronic diseases, including genital lesions, chicken pox, glandular fever, and various cancers. Current treatments employ nucleotide, nucleoside or pyrophosphate analogues that specifically inhibit the herpesvirus DNA polymerases. Ultimately, drug-resistant strains emerge from immunocompromised patients to circumvent these inhibitors. As such, it is necessary for further development of drugs against herpesviruses, particularly those that induce cancer.

In the study, published in Nature Microbiology, researchers at the University of Leeds identified a single protein common to all herpesviruses. This protein commandeers a host cell protein complex, human TREX, to stabilise and transport herpesvirus RNA out of the nucleus for translation into viral proteins. By inhibiting the activity of a particular component of the human TREX complex, UAP56, it prevents the common viral protein from taking advantage of its protective effect, thereby inhibiting virus replication and production of infectious particles.

Following these positive results, Dr Richard Foster, who led a team on this study, said, “We still have a lot of work to do, but bringing together a target point and a compound is a significant finding. Now our job is to improve the quality and potency of the compound before it can operate as a future antiviral drug.”

Read the press release

Read the full article: Schumann et al. 2016. Nature Microbiology doi: 10.1038/nmicrobiol.2016.201

Image credits: Upper chest figure - Jolles et aI; DNA and medicine - Pixabay; Cancer ribbons - Howardrv/Flickr; Human herpesvirus 6 (HHV6) - AJ Cann/Flickr CC-BY-NC-SA.